Cancer is second only to cardiovascular disease as the leading cause of death in the United States. The American Cancer Society estimated that 1.4 million new cancer cases would be diagnosed and 565,000 people would die of cancer in 2006 (American Cancer Society, Cancer Facts and Figures 2006, Atlanta, Ga.). The National Cancer Institute estimated that in January 2002, approximately 10.1 million living Americans had a history of cancer. The National Institutes of Health estimate direct medical costs of cancer as over $100 billion per year with an additional $100 billion in indirect costs due to lost productivity—the largest such costs of any major disease.
Cancer is a process by which the controlling mechanisms that regulate cell growth and differentiation are impaired, resulting in a failure to control cell turnover and growth. This lack of control can cause a tumor to grow progressively, enlarging and occupying space in vital areas of the body. If the tumor invades surrounding tissue and is transported to distant sites, death of the individual can result.
Different classes of pyridyl cyanoguanidines with antiproliferative activity are disclosed in, for instance, EP 660 823, WO 98/54141, WO 98/54143, WO 98/54144, WO 98/54145, WO 00/61559 and WO 00/61561. The structure-activity relationships (SAR) of such compounds are discussed in C. Schou et al., Bioorganic and Medicinal Chemistry Letters 7(24), 1997, pp. 3095-3100, in which the antiproliferative effect of a number of pyridyl cyanoguanidines was tested in vitro on different human lung and breast cancer cell lines as well as on normal human fibroblasts. The compounds were also tested in vivo in nude mice carrying a human lung cancer tumor xenograft. Based on the SAR analysis, a specific compound (N-(6-(4-chlorophenoxy)hexyl)-N′-cyano-N″-(4-pyridyl)guanidine) was selected for its high antiproliferative activity in vitro and potent antitumor activity in the nude mouse model.
Hjarnaa et al, Cancer Res. 59, 1999, pp. 5751-5757, describe the results of further testing of the compound N-(6-(4-chlorophenoxy)hexyl)-N′-cyano-N″-(4-pyridyl)guanidine in in vitro and in vivo tests. The compound exhibited a potency in vitro which was comparable to that of the reference cytostatic agents daunorubicin and paclitaxel, while showing considerably less antiproliferative activity on normal human endothelial cells. In in vivo tests using nude mice transplanted with human tumor cells, the compound showed substantial antitumor activity, also against tumor cells that were resistant to conventional anticancer drugs such as paclitaxel.
NAD+ can be synthesized through a de novo pathway from tryptophan or through a salvage pathway from two precursors, nicotinamide (the process which is herein referred to as the “nicotinamide salvage pathway”) and nicotinic acid (the process which is herein referred to as the “nicotinic acid salvage pathway” or simply as “nicotinic acid pathway”). In the nicotinamide salvage pathway, nicotinamide is converted to NAD+ by two enzymes, nicotinamide phosphoribosyl transferase (NMPRT) and nicotinamide mononucleotide adenyltransferase, which convert nicotinamide to nicotinamide mononucleotide and nicotinamide mononucleotide to NAD+, respectively. In the nicotinic acid salvage pathway, nicotinic acid is converted to NAD+ by three enzymes: nicotinic acid phosphoribosyl transferase (NAPRT), nicotinic acid mononucleotide adenyltransferase, and NAD+ synthetase, which convert nicotinic acid to nicotinic acid mononucleotide, nicotinic acid mononucleotide to nicotinic acid adenine dinucleotide, and nicotinic acid adenine dinucleotide to NAD+, respectively (see Hara et al. (2007), “Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells”, Journal of Biological Chemistry, 282 (34): 24574-24582).
Tumor cells have a high rate of NAD+ turnover due to elevated ADP-ribosylation activity, predominantly mediated by the poly(ADP-ribose) polymerases (PARPs). Poly ADP-ribosylation of specific target proteins is crucial for genome stability, DNA repair, telomere maintenance, cell death and other biological functions. Proteins that bind mono and poly(ADP-ribose) have been identified, suggesting that these molecules may have important cellular functions themselves. DNA damage can stimulate NAD+ biosynthesis. Expression levels of NMPRT, which is the rate-limiting enzyme in the salvage pathway from the breakdown product nicotinamide, are upregulated in colorectal cancers, suggesting that NMPRT may be crucial for maintaining cellular NAD+ levels in tumors. NMPRT-deficient mice die during early embryogenesis. (E)-N-[4-(1-benzoylpiperidin-4-yl) butyl]-3-(pyridin-3-yl)acrylamide, also known as FK866, is a potent small-molecule inhibitor of human NMPRT, and the consequent reduction in NAD+ levels can cause apoptosis of tumor cells while having little (toxic) effects on normal cells. This validates NMPRT as a target for the development of novel therapeutic agents (see Khan et al., Expert Opin. Ther. Targets (2007), 11(5):695-705).
Despite the significant research efforts and resources that have been directed towards the development of anti-cancer drugs and improved methods for treating cancer, there remains a need in the art for novel compounds, compositions, or methods that are useful for modulating NMPRT activity, decreasing cellular DNA repair, decreasing NAD+ biosynthesis, sensitizing a patient to DNA damaging therapy, or increasing efficacy of radiation therapy. In addition, there remains a need for novel compounds, compositions and methods that are useful for treating a cancer deficient in nicotinic acid pathway.
Citation of any reference in Section 3 of this application is not an admission that the reference is prior art.